206
J.Med. Chem. 1984,27, 206-212
Training Grant 1341 (W.J.B.), Research Grant NS 12429
(G.L.G.), and from the University of Kansas General Research Fund (G.L.G.) is gratefully acknowledged.
Registry No. 1, 65379-06-8; 2, 87532-76-1; 3, 87532-77-2; 4,
65379-07-9; 5, 87532-78-3; 6, 87532-79-4; 7, 87532-80-7; 8,
87532-81-8; 9, 87532-82-9; 10, 87532-83-0; 11, 68475-16-1; 12,
68475-11-6; 13, 68475-10-5; 14, 68475-17-2; 15, 68475-18-3; 16,
87532-84-1; 17, 68475-19-4; 18, 774-40-3; 19, 33224-90-7; 20,
87532-85-2; 21, 87532-86-3; 22, 65379-04-6; 23, 65379-03-5; 24,
87532-87-4; 2-pentyloxycarbonyl chloride, 20412-35-5; ethyl
chloroformate, 541-41-3; chloroacetyl chloride, 79-04-9; bromoacetyl bromide, 598-21-0; acetyl bromide, 506-96-7; acrylonitrile,
107-13-1.
Synthesis of Imidazo[ 1,2-a Ipyrazine Derivatives with Uterine-Relaxing,
Antibronchospastic, and Cardiac-Stimulating Properties
Claire Sablayrolles,**?
Gerard H. Cros,*J Jean Claude Milhavet,+Eliane Rechenq,? Jean-Pierre Chapat,?
Maurice Boucard,t Jean J. Serrano,t and John H. McNeill*J
Laboratoire de Chirnie Organique Pharmaceutique and Laboratoire de Pharrnacodynamie, Faculte de Pharmacie, 34060
Montpellier-Cedex, France, and Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of
British Columbia, Vancouver, British Columbia, Canada, V6T 1 W5. Received July 29, 1982
A series of imidazo[ 1,2-a]pyrazine derivatives was synthesized by condensation of a-halogenocarbonyl compounds
and aminopyrazines. Various compounds resulted from competitive reactions or reagent isomerization and demonstrated in vitro uterine-relaxing and in vivo antibronchospastic activities. On isolated atria, 5-bromoimidazo[ 1,2-a]pyrazine showed positive chronotropic and inotropic properties; the latter was associated with an increase
in the cyclic AMP tissue concentration. Potentiation of the isoproterenol positive inotropic effect of 5-bromopositive inotropic effect by
imidazo[ l,2-a]pyrazine and the lack of blockade of the 5-bromoimidazo[l,2-a]pyrazine
propranolol suggested phosphodiesterase-inhibiting properties.
Several structural analogues of purines have been recently developed as potential chemotherapeutic and
pharmacologically active agent~.l-~Among the deazapurine homologues containing the pyrazine ring, only a few
studies on the imidazo[1,2-a]pyrazine have been reported.4-8 Recent work has shown that some compounds
exhibit various pharmacological properties:JO such as
antiinflammatoryl1J2 and @-blockingacti~ities.~
The present work described the synthesis of a series of
deazapurine derivatives, showing their uterine-relaxing and
antibronchospastic properties and analyzing the cardiac
properties and the mechanism of action of one compound
of the series, the 5-bromoimidazo[l,2-a]pyrazine
(14).
Chemistry. Condensation of a-halogenocarbonyl compounds with aminopyrazine led to some substituted imidazo[l,2-a]pyrazines, without the Dimroth-type rearrangement5 (Scheme I).
In the case
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